摘要
本文采用大孔吸附树脂分离纯化山楂叶总黄酮,通过采用单向灌流模型、翻转肠囊模型和大鼠原位肠袢模型进行山楂叶总黄酮的肠吸收研究,并进行了山楂叶总黄酮(HLF)的药动学研究,结果表明:山楂叶总黄酮中的指标成分牡荆素鼠李糖苷(VRH)在大鼠小肠的转运机制为被动扩散为主,P-糖蛋白介导了牡荆素鼠李糖苷的小肠吸收;山楂叶总黄酮中牡荆素鼠李糖苷在大鼠体内消除较快,具有线性药动学特征。此外,采用三因素三水平的Box-Behnken设计,优化山楂叶总黄酮缓释微丸的包衣液处方,使用空气悬浮流化床包衣法,制备了山楂叶总黄酮缓释微丸,并对其质量进行考察。
D101 macroporus resin was used to isolate and purifying total flavonoids from leaves of Crataegus Pinnatifida Bge., ie. HLF. The in situ rat single-pass intestinal perfusion model, the in vitro rat everted gut sac model and the in situ rat loop model were used to study the intestinal absorption of HLF. Pharmacokinetics study on HLF was also investigated. The results showed that Passive diffusion dominates the absorptive transport behavior of VRH in HLF. The absorption of VRH in HLF is mediated by the efflux transport system, P-gp. VRH in HLF was eliminated quickly in rat plasma, and VRH has linear pharmacokinetics characteristics. The coating solution formulation of HLF sustained pellets was optimized with a three-factor, three-level Box-Behnken design. HLF sustained pellets were prepared by the film coating method of air floating fluid bed. The quality of HLF sustained pellets was also investigated.
引文
1 英锡相,李绍雄,林延会. 山楂叶植物学及化学成分研究近况[J]. 辽宁中医学院学报, 2001, 3(2): 98-99.
2 Rehwald A, Meier B, Sticher O. Qualitative and quantitative reversed-phase high-performance liquid chromatography of flavonoids in Crataegus leaves and flowers[J]. J Chromatogr A, 1994, 677: 25-33.
3 Liu RH, Yu BY, Qiu SX, et al. Comparative analysis of eight major polyphenolic components in leaves of Crataegus L. by HPLC[J]. Chin J Nat Med, 2005, 3(3):162-167.
4 陈四平, 臧亚茹. 山楂叶的研究进展[J]. 承德医学院学报, 2003,20(2): 164-165.
5 张雷, 邓同乐, 严伟民, 等. 山楂叶总黄酮对脑缺血的保护作用[J]. 上海中医药杂志, 2004, 38(8): 55-57.
6 叶希韵, 王耀发. 山楂叶总黄酮对血管内皮细胞氧化损伤的保护作用[J]. 中国现代应用药学杂志, 2002, 19(4): 265-268.
7 Uchiyama T, Sugiyama T, Quan YS, et al. Enhanced permeability of insulin acrossthe rat intestinal membrane by various absorption enhancers: their intestinal mucosal toxicity and absorption-enhancing mechanism of n-lauryl-beta-D-maltopyranoside[J]. J Pharm Pharmacol, 1999, 51:1241-1247.
8 Berggren S, Hoogstraate J, Fagerholm U, et al. Characterization of jejunal absorption and apical efflux of orpivacaine, lidocaine and bupivacaine in the rat using in situ and in vitro absorption models[J]. Eur J Pharm Sci, 2004, 21, 553-560.
9 Guo J, Ping Q, Dong J, Qi S, et al. Transport of leuprolide across rat intestine, rabbit intestine and Caco-2 cell monolayer[J]. Inter J Pharm, 2004, 278, 415-422.
10 Barthe L, Bessouet M, Woodley JF, et al. The improved everted gut sac: a simple method to study intestinal P-glycoprotein[J]. Int J Pharm, 1998, 173, 255–258.
11 Sha XY, Fang XL. Transport characteristics of 9-nitrocamptothecin in the human intestinal cell line Caco-2 and everted gut sacs[J]. Inter J Pharm, 2004, 272,161-171.
12 Hebert MF. Contribution of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery[J]. Adv Drug Deliv Rev, 1997, 27, 201–214.
13 Cummins CL, Salphati L, Reid MJ. In vivo modulation of intestinal CYP3A metabolism by P - glycoprotein: studies using the rat single - pass intestinal perfusion model[J] . J Pharmacol Exp Ther, 2003, 305, 306 - 314.
14 Varma MVS, Kapoor N, Sarkar M, et al. Simultaneous determination of digoxin and permeability markers in rat in situ intestinal perfusion samples by RP-HPLC[J]. J Chromatogr B, 2004, 813, 347-352.
15 Grassi M, Cadelli G. Theoretical considerations on the in vivo intestinal permeability determination by means of the single pass and recirculation techniques[J]. Int J Pharm, 2001, 229, 95-105.
16 Baluom M, Friedman DI, Rubinstein A. Absorption enhancement of calcitonin in the rat intestine by carbopol-containing submicron emulsions[J]. Inter J Pharm, 1997, 154:235-243.
17 Takano M, Koyama Y, Nishikawa H, et al. Segment-selective absorption of lysozyme in the intestine[J]. Eur J Pharmacol, 2004, 502:149-155.
18 Kamio Y, Saito Y, Utoguchi N, et al. Epinephrine is an enhancer of rat intestinal absorption[J]. J Contr Rel, 2005, 102: 563-568.
19 杨海涛, 王广基. Caco-2 单层细胞模型及其在药学中的应用[J]. 药学学报, 2000, 35(10): 797-800.
20 Artursson P, Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial(Caco-2) cells[J]. Biochem Biophy Res Commun, 1991, 175: 880-885.
21 胡晓渝,姚彤炜,曾苏. Caco-2 细胞系及其在药物吸收、代谢中的应用[J].中国现代应用药学杂志, 2002, 19(2): 88-90.
22 Walgren RA, Karnaky KJ, Lindenmayer GE, et al. Efflux of Dietary flavonoid guercetin 4’-β-glucoside across human intestinal Caco-2 cell monolayers by apical multidrug resistance associated protein-2[J]. J Pharmcol Exp Ther, 2000, 294(3): 830-836.
23 Annaert P, Gelder JV, Naesens L et al. Carrier mechanism involved in the transepithelial transport of bis (POM)-PMEA and its metabolites across Caco-2 monolayers[J]. Pharm Res, 1998, 15(8): 1168-1173.
1 丁杏苞,姜岩青,仲英,等.山楂叶化学成分的研究[J].中国中药杂志,1990,15(5):39-41.
2 仲英,杨尚军,王菊,等.高效液相色谱法测定山楂叶总黄酮中牡荆素含量[J].时珍国医国药,2000,11(10):871-872.
3 王冬梅,尉芹,马希汉.大孔吸附树脂在药用植物有效成分分离的应用[J]. 西北林学院学报,2002,17(1):60-63.
4 孙越,曹喜红,潘艳丽.大孔吸附树脂在中草药研究中的应用[J].中医药信息,2002,9(2):23-25.
5 王雅君,郭澄,刘皋林,等. 应用大孔吸附树脂吸附分离技术制备菟丝子总黄酮的研究[J]. 中药材, 2004, 27(11): 861-862.
6 中国药典委员会. 中国药典,第一卷[S]. 化学工业出版社, 北京, 2005.
7 瞿发林,刘桂永,赵汗清,等. 郁福来胶囊质量标准[J]. 中国医院药学杂志,2005,25(1):54-56.
1 Amidon G L, Lennern?s H, Shah V P, et al. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability[J]. Pharm. Res, 1995, 12: 413–420.
2 Fagerholm U, Johansson M, Lennern?s H. Comparison between permeability coefficients in rat and human jejunum[J]. Pharm Res, 1996, 13: 1336–1342.
3 Fricker G, Drewe J, Huwyler J, et al. Relevance of P-glycoprotein for the enteral absorption of cyclosporine A: in vitro-in vivo correlation[J]. Br J Pharmacol, 1996, 118:1841- 1849 .
4 Berggren S, Hoogstraate J, Fagerholm U, et al. Characterization of jejunal absorption and apical efflux of orpivacaine, lidocaine and bupivacaine in the rat using in situ and in vitro absorption models[J]. Eur J Pharm Sci, 2004, 21: 553-560
5 Varma M V S, Sarkar M, Kapoor N, Panchagnula R. PH-dependent functional activity of P-glycoprotein in limiting intestinal absorption of protic drugs 1: Simultaneous determination of quinidine and permeability markers in rat in situ perfusion samples[J]. J Chromatogr B, 2005, 816: 243-249.
6 英锡相,李绍雄,林延会,等. 山楂叶植物学及化学成分研究近况[J]. 辽宁中医学院学报,2001, 3(2): 98-99.
7 陈四平,臧亚茹. 山楂叶研究进展[J]. 承德医学院学报,2003,20(2): 164-165.
8 Berggren S, Hoogstraate J, Fagerholm U, et al. Characterization of jejunal absorption and apical efflux of ropivacaine, lidocaine and bupivacaine in the rat using in situ and in vitro absorption models [J]. Eur J Pharm Sci, 2004, 21: 553-560.
9 胡一桥,郑梁元,钱陈钦,等. 离子型药物酚红的小肠吸收研究[J]. 中国药科大学学报,1996,27(6):355-359.
10 Stewart BH, Chan OH, Jezyk N, et al. Discrimination between drug candidates using models for evaluation of intestinal absorption[J]. Adv Drug Deliv Rev, 1997,23, 27-45.
11 Varma MVS, Khandavilli S, Ashokraj Y, et al. Biopharmaceutic classification system: a scientific framework for pharmacokinetic optimization in drug research[J]. Curr Drug Metab, 2004, 5, 375–388.
12 Grassi M, Cadelli G. Theoretical considerations on the in vivo intestinal permeability determination by means of the single pass and recirculation techniques[J]. Int J Pharm, 2001, 229, 95-105.
13 Salphati L, Childers K, Pan L, et al. Evaluation of a single-pass intestinal-perfusion method in rat for the prediction of absorption in man[J]. J Pharm Pharmacol., 2001, 53, 1007-1013.
14 Artursson P, Ungell AL, L?froth JE. Selective paracellular permeability in two models of intestinal absorption: cultured monolayers of human intestinal epithelial cells and rat intestinal segments[J]. Pharm Res, 1993, 10 , 1123–1129.
15 Troutman MD, Thakker DR. Novel experimental parameters to quantify the modulation of absorption and secretary transport of compounds by P-glycoprotein in cell culture models of intestinal epithelium. Pharm Res, 2003,20, 1200-1209.
16 尹茶,吴玉田. 高效毛细管电泳技术及其在中药分析中的应用[J]. 药物分析杂志, 1999 , 19 (3) :209-216.
1 英锡相,李绍维,林延会,等. 山楂叶植物学及化学成分研究近况[J]. 辽宁中医学院学报, 2001, 3(2): 98-99.
2 陈四平, 臧亚茹. 山楂叶的研究进展[J]. 承德中医学院学报, 2003,20(2): 164-165.
3 Fricker G, Drewe J, Huwyler J, et al. Relevance of P-glycoprotein for the enteral absorption of cyclosporine A: in vitro-in vivo correlation[J]. Br J Pharmacol, 1996, 118(9): 1841-1849
4 Baluom M, Friedman M, Rubinstein A. Improved intestinal absorption of sulpiride in rats with synchronized oral delivery systems[J]. J Controlled Release, 2001, 70(2):139-147
5 Guo J, Ping Q, Dong J, et al. Transport of leuprolide across rat intestine, rabbit intestine and Caco-2 cell monolayer [J]. Inter J Pharm, 2004, 278: 415-422.
6 Barthe L, Bessouet M, Woodley JF, et al.. The improved everted gut sac: a simple method to study intestinal P-glycoprotein[J]. Int J Pharm, 1998, 173, 255–258.
7 Sha XY, Fang XL. Transport characteristics of 9-nitrocamptothecin in the human intestinal cell line Caco-2 and everted gut sacs[J]. Inter J Pharm, 2004, 272, 161-171.
8 Thiebault F, Tsuruo T, Hamada H, et al. Cellular localisation of the multidrug resistance gene product P-glycoprotein in normal human tissues[J]. Proc Natl Acad Sci, USA 1987, 84, 7735–7738.
9 Hebert MF. Contribution of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery[J]. Adv Drug Deliv Rev, 1997, 27, 201–214.
10 Benet LZ, Wu CY, Hebert MF, et al. Intestinal drug metabolism and antitransport processes: a potential paridigm shift in oral drug delivery[J]. J Control Release, 1997, 39, 139–143.
11 Watkins PB. The barrier function of CYP3A4 and P-glycoprotein in the small bowel. Adv Drug Deliv Rev, 1997, 27, 161–170.
1 Baluom M, Friedman DI, Rubinstein A. Absorption enhancement of calcitonin in the rat intestine by carbopol-containing submicron emulsions[J]. Inter J Pharm, 1997, 154: 235-243.
2 Takano M, Koyama Y, Nishikawa H, et al. Segment-selective absorption of lysozyme in the intestine[J]. Eur J Pharmacol, 2004, 502:149-155.
3 Kamio Y, Saito Y, Utoguchi N, et al. Epinephrine is an enhancer of rat intestinal absorption[J]. J Contr Rel, 2005, 102: 563-568.
4 刘辉, 潘卫三, 杜蓉, 等. 几种酶抑制剂对胰岛素肠道吸收的影响[J]. 药学学报, 2004, 39(2): 140-143.
5 Prueksaritanont T, Deluna P, Gorham LM, et al. In vitro and in vivo evaluations of intestinal barriers for the zwitterion L-767,679 and its carboxyl ester prodrug L-775,318 roles of efflux and metabolism[J]. Drug Metab Dispos, 1998, 26: 520-527.
6 Stewart BH, Chan OH, Jezyk N, et al. Discrimination between drug candidates using models for evaluation of intestinal absorption[J]. Adv Drug Deliv Rev, 1997,23, 27-45.
7 Varma MVS, Khandavilli S, Ashokraj Y, et al. Biopharmaceutic classification system: a scientific framework for pharmacokinetic optimization in drug research[J]. Curr Drug Metab, 2004, 5, 375–388.
8 Fagerholm U, Johansson M, Lennern?s H. Comparison between permeability coefficients in rat and human jejunum[J]. Pharm Res, 1996,13, 1336–1342.
1 中国药典委员会. 中国药典,第一卷[S]. 化学工业出版社, 北京, 2005.
2 Rehwald A, Meier B, Sticher O. Qualitative and quantitative reversed-phase high-performance liquid chromatography of flavonoids in Crataegus leaves and flowers[J]. J Chromatogr A, 1994, 677: 25-33.
3 Liu RH, Yu BY, Qiu SX, et al. Comparative analysis of eight major polyphenolic components in leaves of Crataegus L. by HPLC[J]. Chin J Nat Med, 2005, 3(3):162-167.
4 英锡相,李绍雄,林延会. 山楂叶植物学及化学成分研究近况[J]. 辽宁中医学院学报, 2001, 3(2): 98-99.
5 陈四平, 臧亚茹. 山楂叶的研究进展[J]. 承德医学院学报, 2003,20(2): 164-165.
6 Guo Ma, Xue-Hua Jiang, Zhuo Chen, et al. Simultaneous determination of vitexin-4 〃 -O-glucoside and vitexin-2 〃 -O-rhamnoside from hawthorn leaves flavonoids in rat plasma by HPLC method and its application to pharmacokinetic studies. J Pharm Biomed Anal, 2007, 44: 243-249.
7 苏娟, 张卫东, 周耘, 等. HPLC 测定益心酮滴丸中的黄酮苷[J]. 中国中药杂志, 2004, 29(6): 525-527.
8 Chang Q, Zhu M, Zuo Z, et al. High-performance liquid chromatographic method for simultaneous determination of hawthorn active components in rat plasma[J]. J Chromatogr B Biomed Sci Appl, 2001, 760: 227-235.
9 朴晋华,董培智,高天红, 等. 益心酮片对大鼠心肌缺血的保护作用[J]. 中国中药杂志, 2003, 28(5): 442-445.
10 张雷, 邓同乐, 严伟民, 等. 山楂叶总黄酮对脑缺血的保护作用[J]. 上海中医药杂志, 2004, 38(8): 55-57.
1 Lippold BC, Gunder W, Lippold BH. Drug release from diffusion pellets coated with the aqueous ethyl cellulose dispersion aquacoat ECD-30 and 20% dibutyl sebacate as plasticizer: partion mechanism and pore diffusion[J]. Eur J Pharm Biopharm, 1999, 47, 27–32.
2 Wesseling M, Bodmeier R. Drug release from beads coated with an aqueous colloidal ethylcellulose dispersion, Aquacoat, or an organic ethylcellulose solution[J]. Eur J Pharm Biopharm, 1999, 47, 33–38.
3 Lehmann K, Almus M, B?ssler H. Practical course in film coating of pharmaceutical dosage forms with Eudragit, Information brochure[M], R?hm GmbH, Darmstadt, pp. 1–12.
4 Petereit HU, Weisbrod W. Formulation and process considerations affecting the stability of solid dosage forms formulated with methacrylate copolymers[J]. Eur J Pharm Biopharm, 47, 15–25.
5 Lehmann, K. Coating of multiparticulates using polymeric solution. In: Ghebre-Sellassie, I. (Ed.) [M], Pharmaceutical Pelletization Tehnology. Marcel Dekker, New York, 1989, pp. 51–77.
6 Harris MR, Ghebre-Sellassie I. Aqueous polymeric coating for modified release oral dosage forms. In: McGinity, J.W. (Ed.), Aqueous Polymeric Coating for Pharmaceutical Dosage Forms[M]. Marcel Dekker, New York, 1997, pp. 81–101.
7 Follonier N, Doelker E. Biopharmaceutical comparison of oral multiple-unit andsingle unit sustained release dosage forms[J]. STP Pharm. Sci., 1992, 2, 141–158.
8 Daumesnil R. Multiparticulate Oral Drug Delivery[M]. Marcel Dekker, New York, 1994, pp. 457–474.
9 陈挺, 陈庆华. 盐酸苯丙醇胺微丸的制备工艺研究[J ] . 中国医药工业杂志, 1999, 30 (8) : 345-348.
10 Kramar A, Turk S, Vrecer F. Statistical optimization of diclofenac sustained release pellets coated with polymethacrylic films[J]. Inter. J. Pharm. 2003, 256, 43-52.
11 胡晋红, 张立强, 李珍, 等. 盐酸氨溴索缓释胶囊的研制[J]. 中国医药工业杂志, 2001, 32(11): 500-502.
12 陆彬主编.药物新剂型与新技术[M].人民卫生出版社. 1998. 300-301.
13 Richard. W. Korsmeyer, Robert Gurny, Eric Doelker, et al. Mechanism of solute release from porous hydrophilic polymers[J]. Inter J Pharm, 1983 , 15: 25-35.
14 Judit Dredan, Istvan Antal and Istvan Racz. Evaluation of mathematical models describing drug release from lipophilic matrices[J]. Inter J Pharm, 1996 (145): 61-64.
15 Nutan MTH, Soliman MS, Taha EI, et al. Optimization and characterization of controlled release multi-particulate beads coated with starch acetate[J]. Inter J Pharm, 2005, 294, 89-101.
1 谷黎红. 大丁草中抗菌活性成分的研究: 人肠道微生物对大丁甙及其类似物的代谢研究[J]. 药学学报, 1988, 23(7): 511-515.
2 陈英杰. 20(s)- 人参皂苷 Rg2 的代谢产物研究[J]. 沈阳药学院学报, 1987,4(3): 202-204.
3 Liu Y, Hu M. Absorption and metabolism of flavonoids in the caco-2 cell culture model and a perused rat intestinal model[J]. Drug Metab Dispos, 2002, 30(4): 370-377.
4 Strugala GJ, Stahl R, Elsenhans B, et al. Small-intestinal transfer mechanism of prunasin, the primary metabolite of the cyanogenic glycoside amygdalin[J]. Human & Exp Toxicol, 1995, 14(11): 895-899.
5 邱峰, 陈英杰, 鹿野美弘, 等. 淫羊藿苷在大鼠体内的代谢[J]. 药学学报, 1999, 34(3): 222-226.
6 刘铁汉, 王毅, 王本祥, 等. 淫羊藿苷的肠菌代谢研究Ⅰ.肠内细菌对淫羊藿苷的代谢转化[J]. 中草药, 2000, 31(11): 834-837.
7 服部征雄. 关于肠内厌氧菌代谢反应[J]. Methods in Kampo Pharmacology, 1997, 1: 15-23.
8 贺玉琢. 葡糖苷为天然前体药物—以无菌及感染人肠内细菌大鼠模型予以证实[J]. 国外医学中医中药分册, 1999, 21(3):14-18.
9 Koyama E, Sakai N, Ohori Y, et al. Absorption and metabolism of glycosidic sweeteners of stevia mixture and their aglycone, steviol, in rats and humans[J]. Food Chem Toxicol, 2003, 41(6):875-883.
10 Mutlib AE, Cheung HT, Watson TR. In vivo and in vitro metabolism of gomphoside, a cardiotonic steroid with doubly-linked sugar[J]. J steroid Biochem. 1987, 28(1): 65-75.
11 诸敏, 姚彤炜, 曾苏. 银杏黄酮的体外Ⅱ相代谢及其临床应用[J]. 药学学报, 2003, 38(12): 938-941.
12 Allen RH, Robert SB. Caco-2 cell momolayers as a model for drug transport across the intestinal mucosa[J]. Pharm Res, 1990,7(9): 902-910
13 Steensma A, Noteborn HP, Jagy RC, et al. Bioavailability of genistein,daidzein,and their glycosides in intestinal epithelial Caco-2 cells[J]. Environ Toxicol Pharmacol, 1999,7(3), 209-212.
14 Steensma A, Noteborna HP, Kuipera HA. Comparison of Caco-2, IEC-18 and HCEC cell lines as a model for intestinal absorption of genistein, daidzein and their glycosides[J]. Environ Toxicol Pharmacol, 2004, 16(3): 131-139.
15 Annaert P, Gelder JV, Naesens L et al. Carrier mechanism involved in the transepithelial transport of bis (POM)-PMEA and its metabolites across Caco-2 monolayers[J]. Pharm Res, 1998, 15(8): 1168-1173.
16 Murota K,Terao J. Antioxidative flavonoid quercetin: implication of its intestinal absorption and metabolism[J]. Archiv Biochem Biophy, 2003, 417(1):12-17.
17 Walgren RA, Karnaky KJ, Lindenmayer GE, et al. Efflux of Dietary flavonoid guercetin 4’-β-glucoside across human intestinal Caco-2 cell monolayers by apical multidrug resistance associated protein-2[J]. J Pharmcol Exp Ther, 2000, 294(3): 830-836.
18 Kim M, Kometani T, Okada S, et al. Permeation of hesperidin glycosides across Caco-2 cell monolayers via the paracellular pathway[J]. Biosci Biotechnol Biochem. 1999, 63(12): 2183-2188.
19 郭涛. Caco-2 细胞模型在药物动力学研究中的应用[J]. 中国药师, 2003, 6(12): 774-776.
20 王金辉, 李铣. 拟人参皂苷 F11 在大鼠体内的药物代谢研究[J]. 药学学报, 2001, 36(6): 427-431.
21 Karikura M, Toshio M, Hisayuki T. Studides on abpsorption, distribution, excretion and metabolism of ginseng saponins. Ⅵ . The decomposition products of ginsenoside Rb2 in the stomach of rats[J]. Chem Pharm Bull, 1991,39(2): 400-404.
22 Tsutomu O, Hisayuki T, Yoshi T, et al. Studied on the absorption, distribution, excretion and metabolism of ginseng saponins. Ⅳ. Decomposition of ginsenoside Rg1 and RB1 in the digestive tract of rats[J]. Chem Pharm Bull, 1983,31(10): 3691-3696.
23 车庆明, 黄新立, 李艳梅,等. 黄芩苷的药物代谢产物研究[J]. 中国中药杂志, 2001, 26(11): 768-769.
24 Zhou YJ, Che QM, Xu SX. Metabolites of baicalein in human urine[J]. Pharmazie, 2000, 55(8): 626-627.
25 Rasmussen SE, Breinholt VM. Non-nutritive bioactive constituents of plants: bioavailability of flavonoids[J]. Int J Vitamin Nutr Res, 2003, 73(2): 101-111.
26 Tsuda T, Horio F, Osawa T. Absorption and metabolism of cyanidin 3-O-β-D-glucoside in rats[J]. FEBS letters, 1999, 449(2): 179-182.
27 Yasuda T, Mizunuma S, Kano Y, et al. Urinary and biliary metabolites of genistein in rats[J]. Biolo & Pharm Bull, 1996, 19(3): 413-417.
28 Yasuda T, Kano Y, Saito K, et al. Urinary and biliary metabolites of puerarin in rats[J]. Biolo & Pharm Bull, 1995, 18(2): 300-303.
29 De Witte P. Metabolism and pharmacokinetics of anthranoids[J]. Pharmacol, 1993, 47(supplement 1):86-97.
30 Fotsch G, Pfeifer, S. The biotransformation of leiocarposide and salicin phenol glycosides-examples for special consideration of the absprption and metabolism of glyxosidec compounds[J]. Die Pharmazie, 1989, 44(10): 710-715.
